Tyrosine kinases are expressed by many human cancers. These enzymes are attractive targets for the development of anticancer drugs, as it has been possible to optimize compounds with excellent inhibitory potency and selectivity to individual target tyrosine kinases. The utility of this approach has been highlighted by the success of imatinib mesylate (Gleevec™) in the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs).
Expression of tyrosine kinases is ubiquitous in both cancers and normal tissues. Therefore, the efficacy of a kinase inhibitor is dependent on two factors: 1) the degree to which the target kinase is activated in a particular cancer, and 2) the degree to which the growth and survival of the cancer cells is dependent on the activated target kinase.
Gastrointestinal stromal tumors provide an excellent example of this principle. KIT tyrosine kinase is detectable by immunohistochemistry in a wide variety of cancers and normal tissues, but mutations of the KIT gene that yield constitutively active KIT kinase are found in only a small subset of tumors (Heinrich et al., J. Clin. Oncol., 20: 1692-1703, 2002). More than 85% of GISTs harbor such activating mutations (Blanke et al., Proceedings of ASCO 20, 1a-1a. 2001; Heinrich et al., J. Clin. Oncol., 20: 1692-1703, 2002; Hirota et al., J. Pathol., 193: 505-510, 2001; Rubin et al., Cancer Res, 61: 8118-8121, 2001) and, correspondingly, phosphorylation of KIT kinase (a marker of activation) was recently demonstrated in most fresh-frozen GIST specimens (Rubin et al., Cancer Res, 61: 8118-8121, 2001). Such phosphorylation of KIT is rarely observed in other cancer specimens. Recent success in the treatment of advanced malignant GISTs with imatinib mesylate is thought to reflect an important role of KIT activation in the growth and/or survival of GIST tumor cells (Blanke et al., Proceedings of ASCO 20, 1a-1a. 2001; Joensuu et al., N Engl J Med, 1052: 1052-1056, 2001; Van Oosterom et al., Lancet, 358:1421-1423, 2001). The observation that treatment results with imatinib mesylate are significantly better for tumors with evidence of mutational activation of KIT than for tumors with no KIT mutation further supports this view (Heinrich et al., J. Clin. Oncol., 20: 1692-1703, 2002). Thus, in the case of GISTs, testing of clinical specimens for genomic mutations resulting in tyrosine kinase activation will be useful in determining which patients are most likely to respond to a tyrosine kinase inhibitor.
The PDGFRA (or PDGFR-α) protein is a type III receptor tyrosine kinase with homology to KIT, FLT3, CSF1-R and PDGFRβ (PDGFRB). Although PDGFRA activation has been hypothesized to be involved in certain cancers, most notably gliomas, evidence of genomic activation in human cancer has only recently been reported in two cases of myeloproliferative disease associated with translocation of the BCR and PDGFRA genes.